8 research outputs found
Recommended from our members
DIAPH3 Governs the Cellular Transition to the Amoeboid Tumour Phenotype
Therapies for most malignancies are generally ineffective once metastasis occurs. While tumour cells migrate through tissues using diverse strategies, the signalling networks controlling such behaviours in human tumours are poorly understood. Here we define a role for the Diaphanous-related formin-3 (DIAPH3) as a non-canonical regulator of metastasis that restrains conversion to amoeboid cell behaviour in multiple cancer types. The DIAPH3 locus is close to RB1, within a narrow consensus region of deletion on chromosome 13q in prostate, breast and hepatocellular carcinomas. DIAPH3 silencing in human carcinoma cells destabilized microtubules and induced defective endocytic trafficking, endosomal accumulation of EGFR, and hyperactivation of EGFR/MEK/ERK signalling. Silencing also evoked amoeboid properties, increased invasion and promoted metastasis in mice. In human tumours, DIAPH3 down-regulation was associated with aggressive or metastatic disease. DIAPH3-silenced cells were sensitive to MEK inhibition, but showed reduced sensitivity to EGFR inhibition. These findings have implications for understanding mechanisms of metastasis, and suggest that identifying patients with chromosomal deletions at DIAPH3 may have prognostic value
Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate-cancer patients
Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction
of prostate-cancer patients than the fraction of patients who progress to metastatic disease.
To provide a better understanding of these cells, we have characterized their genomic alterations.
We first present an array comparative genomic hybridization method capable of detecting
genomic changes in the small number of disseminated cells (10-20) that can typically be obtained
from bone-marrow aspirates of prostate-cancer patients. We show multiple regions of
copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain,
and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from
11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of
disseminated cells from patients with organ-confined disease. However, we identify changes
shared by these samples with their corresponding primary tumors and prostate-cancer alterations
reported in the literature, evidence that these cells, like those in advanced disease, are
disseminated tumor cells (DTCs). We also demonstrate that DTCs from patients with advanced
and localized disease share several abnormalities, including losses containing cell-adhesion
genes and alterations reported to associate with progressive disease. These shared alterations
might confer the capability to disseminate or establish secondary disease. Overall, the spectrum
of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and variation
in that capacity in DTCs from localized disease. Our analysis lays the foundation for elucidation
of the relationship between DTC genomic alterations and progressive prostate cancer